Table Of ContentPreface
Thehumanbodyisprimarilygovernedbytwointri- a separate chapter on sellar masses, key elements of
cate communicating networks: the nervous system clinical history, biochemical and radiological assess-
andtheendocrinesystem.Thestudyoftheinterrela- ment as well as epidemiology of sellar masses are
tionshipofthesetwonetworkscreatedthediscipline discussed. The clinical implications of various phy-
of neuroendocrinology. Recent advances in this field siological principles as well as cases from our clinics
havetransformedourviewofhowhumanendocrine are included in the text. The text itself is liberally
homeostasis is maintained. For example, the discov- illustrated with full-color, high-resolution images to
eryoftheadipokineleptinrevolutionizedourunder- provide concise summaries of information. Extensive
standing of the neural mechanisms by which we lists of references emphasize original papers based
regulate body weight. A further case is the discovery on human data.
oftheKISS1gene,anditsencodedneuropeptidekis- We intend the book to be useful at multiple
speptin, now recognized as obligatory for successful levels, though it is especially aimed at those stu-
humanreproductivefunction. dents and clinicians not previously exposed to
Althoughseveraltextsarecurrentlyavailablethat a specific course in neuroendocrinology. For exam-
cover the field of clinical neuroendocrinology, they ple, senior medical students making decisions to
are almost exclusively advanced, multi-author books pursue a specialty will find it helpful, as will those
written by experts and largely aimed at medical spe- residentsandclinicalfellowswhoareembarkingon
cialists. While these texts provide a comprehensive their chosen fields. In addition, this book should
clinicaland basicsciencereview ofthesubject,there provide a crucial clinical context for biomedical
is a compelling need for an introductory description science graduate students who may already be
of the human neuroendocrine system in health and familiar with basic science research principles.
disease.Ourbookisthereforedesignedtoemphasize We include an extensive and up-to-date reference
the key physiological principles necessary for an list for each chapter, and additional material is
understanding of various clinical neuroendocrine provided under a further reading list. The latter
disorders. tend to be clinical reviews that may be particularly
Introductory chapters discuss the fundamentals usefultothemoreadvancedreaderandwillprovide
that govern how the hypothalamic–pituitary system a convenient link to the available specialized texts.
interacts with various endocrine target tissues. A selection of review questions is provided at the
Topics include cellular communication, hormone end of each chapter.
receptor systems, hormone assays and a description Thefieldofneuroendocrinologyisarapidlyevol-
of the importance of hormonal secretory rhythms. ving area of health sciences. This introduction to
Subsequent chapters outline the essentials of human clinicalneuroendocrinologyshouldserveasaguide
female reproduction, the regulation of body weight to medical students, clinicians and biomedical
and metabolism with a focus on obesity, the control science students, as well as their teachers, in nego-
of prolactin secretion and the principles of adrenal, tiating a fascinating and essential clinical field of
thyroid and growth hormone physiology. Finally, in study.
ix
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Chapter Basic Principles in Clinical
1
Neuroendocrinology I: Receptor
Mechanisms
Thehomeostaticfunctionsofthebodyareprimarily confronted through addressing the underlying neu-
controlledbyneuronalcellscommunicatingthrough roendocrine principles.
electrical impulses and endocrine cells communicat- Forthemostpart,thebraininfluencesendocrine
ing through chemicals. Neuroendocrinology is the targets in tandem with the pituitary gland; that is,
branchofendocrinologythatisconcernedwithhow pituitary hormone secretion is directed by various
the brain regulates the endocrine milieu. stimuli secreted from hypothalamic neurons. Thus,
An essential and critical characteristic of this neural luteinizing hormone (LH) is released from pituitary
control is that endocrine hormones have profound gonadotropesfollowingstimulationbygonadotropin
effects on brain function through homeostatic feed- releasinghormone(GnRH),aneuropeptideproduced
back systems. An understanding of the chemical by hypothalamic neurons. Figure 1.1 illustrates the
mechanisms that underpin neuroendocrine regula- hypothalamicreleasinghormonesthatregulateante-
tion is critical when dealing with clinical disorders rior pituitary hormone secretion. Note that dopa-
of the neuroendocrine system. For example, the mine – a neurotransmitter – controls prolactin
clinical complications of abnormal growth, thyroid (PRL) secretion. In contrast, posterior pituitary hor-
disorders, obesity and Cushing’s syndrome can be mones,suchasoxytocin,arenotundertheinfluence
HYPOTHALAMUS
Thyrotropin releasing hormone
Growth hormone releasing hormone
Dopamine
Gonadotropin releasing hormone
Somatostatin ANTERIOR
Corticotropin releasing hormone PITUITARY
Growth hormone
Luteinizing hormone
Follicle stimulating hormone
Adrenocorticotropic hormone
Thyroid stimulating hormone
POSTERIOR Prolactin
PITUITARY
Vasopressin
Oxytocin
Figure1.1 Hypothalamicandpituitaryhormonesoftheneuroendocrinesystem.PublicdomainimagesfromLadyofhats:http://en.wikipedia
.org/wiki/File:Endocrine_central_nervous_en.svg.
1
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
G protein-coupled receptor (GPCR) superfamily.
Regulatory
neurons Other hormones, such as leptin, bind to so-called
+
– tyrosine kinase-dependent receptors. An additional,
–
intracellular, superfamily of steroid hormone recep-
torsmediatesthefeedbackeffectsofsteroidhormones
suchasestradiolandcortisolattheleveloftheante-
riorpituitaryandhypothalamus.Thus,aninterplayof
± – fluctuating hormonal levels with receptor sensitivity
GnRH
dictates homeostatic neuroendocrine regulation.
neurons
The following sections will summarize the receptor-
Infundibular
signalingsystemsthat:(a)regulatetargetorganactiv-
nucleus
ity, for example, stimulation of gonadotrophs by
GnRH GnRH acting through cell surface GPCRs; and (b)
Portal
vasculature controlhormonalfeedbackinthehypothalamusand
pituitary, for example, intracellular estradiol recep-
± –
torsinbrainandpituitary.
Anterior
pituitary
1.1 Cell Membrane Receptors
LH/FSH
Peptide hormones, neuropeptides and neurotrans-
mitters are generally water soluble and cannot easily
Estradiol Testosterone
entertheirtargetcells.Theyregulatecellularactivity
Progesterone bybindingtospecificreceptorslocatedintheplasma
membranes of their target cells. In order to induce
Ovary Testis
biochemicalchangeswithinthetargetcell,theyactas
Figure1.2 HomeostaticcontrolofGnRHsecretionandthereproductive
system.SchematicdiagramhighlightingtheroleofGnRHneuronsinthe first messengers to activate an intracellular second
controlofhumanreproduction.Redarrowsindicatethepositiveand messenger, such as cyclic adenosine monophosphate
negativefeedbackeffectsofserumestradiolandprogesteroneexerted
(cAMP). The transduction of information from the
onGnRHsecretion.Thiscontrolisimposedatseverallevels:directlyon
GnRHneurons;atthelevelofgonadotrophs;andonneurons(stimula- firsttothesecondmessengerisaccomplishedthrough
toryandinhibitory)thatregulateGnRHneurons.Bluearrowsillustrate theactivationofmembraneproteins(e.g.,Gproteins)
thenegativefeedbackeffectsoftestosteroneonGnRHreleaseinthe
andenzymes,suchasadenylatecyclase.
male.Abbreviations:GnRH,gonadotropinreleasinghormone;LH,
Luteinizinghormone;FSH,Folliclestimulatinghormone. Thissectionillustratestheroleofmembranerecep-
torsforpeptidehormoneandneurotransmitteraction,
of releasing hormones but instead are secreted the mechanisms by which signal transduction across
directly from hypothalamic neuron terminals in the the cell membrane occurs, the role of G proteins and
posteriorpituitary. receptor tyrosine kinases in this signal transduction,
A typical neuroendocrine feedback network is andthesecondmessengersystemsactivated.
exemplified by the reproductive system in which the
target organs (ovary and testis) respond to gonado- 1.2 G Protein-Coupled Receptors
tropin stimulation by releasing sex hormones (estra-
diol,progesteroneortestosterone)that,inturn,exert GPCRs are characterized by their seven transmem-
negative feedback on the hypothalamus to influence brane domain structures attached to trimeric
secretion of GnRH and LH/follicle stimulating hor- G proteins (Figure 1.3). They bind multiple neuro-
mone (FSH) (see Figure 1.2 and Chapter 3). Other transmitters, hormones and peptides, and control
exampleswillbedescribedinsubsequentchapters. almost all known physiological processes, including
Thetargetorgansensitivitytostimulation,andthe neuroendocrine regulation, cardiovascular function,
neuronal response to hormonal feedback, is depen- behavior and immune function. A variety of
dent upon a variety of receptor mechanisms. For Gproteinstogetherwithreceptors,effectorsandvar-
example,inFigure1.2,theresponseofpituitarygona- iousregulatoryintracellularproteinsarethe compo-
2 dotrophs to stimulation with the peptide GnRH is nents of a complex and versatile signal transduction
governed by specific membrane receptors of the system (for a detailed review see Wettschureck and
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
GnRH
CRH GHRH
TSH GPCR
dopamine
Activated G protein N
Extracellular LI
E
Cytoplasm 12 3546 7 γ γ GHR + SOM
GDP Gα β GTPGαsGα Gαq β + –
Gαs cAMP AC PLC cAMP/Ca2+ Inhibition of
PLC/IP3/Ca2+ cAMP
Gαq PLC
cAMP
Gαi cAMP
+ –
PKA PKC
GH gene Inhibition
Biological Gene expression expression; of
response GH release GH secretion
Nucleus DNA
Figure1.3 SchematicdiagramofGPCRsignalingviaGproteins
andsecondmessengers.GPCRs,intheinactivestate,possessseven GH SECRETION
transmembranedomainscoupledtoaGproteincomplexconsisting
ofα-,β-andγ-subunits,plusamoleculeofGDP.Bindingofaspecific
ligandactivatestheGα-subunitbyreplacingGDPwithGTP,followed
bydissociationoftheβγ-subunit.Thisstepisreversiblefollowing
SOMATOTROPH
dissociationordegradationofthereceptorstimulus.TheGα-subunit
existsasthreeforms:(a)astimulatoryGαsthatincreasescAMP Figure1.4 GPCR-dependentmechanismsregulatingGHsecretion
productionandtheactivationofproteinkinaseA;(b)astimulatory frompituitarysomatotrophs.ReceptorsforGHRHandghrelinare
GαqthatselectivelystimulatesthePLCpathwaytoactivatePKC;and stimulatoryGproteincoupled,linkedtocAMP/PKAandPLC/PKC
(c)aninhibitoryG03B1ipathwaythatinhibitscAMPproduction. signals,respectively.GHRHandghrelinactsynergisticallytoinduce
Theproteinkinasesmayregulateenzymeactivityorgeneexpression intracellularcalciumionmobilizationthat,inturn,controlsGH
viatranscriptionfactors(dottedarrows)thatbindtotargetgenes. secretion.ThesestimulialsoinduceGHgeneexpressionandGH
ExamplesofligandsthatbindtoGPCRsareGnRH,CRH,TSHand synthesisinsomatotrophs.Incontrast,SOMbindstoaninhibitory
dopamine.Imagereproducedwithpermission(Neumannetal.,2014). GPCRthatreducestheaccumulationofcAMP,decreasingtherelease
Abbreviations:AC,adenylatecyclase;GDP,guanosinediphosphate; ofGH(Ben-ShlomoandMelmed,2010).Abbreviations:GPCR,
GnRH,gonadotropinreleasinghormone;GPCR,Gprotein-coupled Gprotein-coupledreceptor;IP3,inositoltriphosphate;PKA,protein
receptor;GTP,guanosinetriphosphate;PIP2,phosphatidylinositol4,5 kinaseA;PKC,proteinkinaseC;SOM,somatostatin.
bisphosphate;PKC,proteinkinaseC;PLC,phospholipaseC.
Offermanns,2005).For thepurposes ofthis chapter, (Figure1.4).Thissystemiscoveredinmoredetailin
Chapter8.Afurtherexampleisthesynergisticstimu-
Figure1.3outlines,ingeneralterms,theprocessesby
lationofadrenocorticotropin(ACTH)frompituitary
which extracellular stimuli are rapidly transduced to
corticotrophsbyCRHandvasopressin(seeChapter5;
intracellular signals that ultimately control gene
expression and biological response. The figure Figure5.5)
includestypicalneuroendocrinestimuli(GnRH,cor- fi
Clinical Signi cance of GPCRs
ticotropin releasing hormone [CRH], thyroid stimu-
lating hormone [TSH] and dopamine) that act via G protein receptors are firmly implicated in all the
GPCRs.Otherexampleswillbecoveredinsubsequent hormonalsystemsdescribedinthis book.Forexam-
chapters. ple, Figure 1.3 illustrates that important neuroendo-
Bywayofillustration,thepituitarysomatotrophis crinemoleculessuchasGnRH(reproductivesystem),
a cell type that utilizes all three of the GPCRs illu- CRH(regulationofthehypothalamic–pituitary–adre-
stratedinFigure1.3;thatis,ghrelinandgrowthhor- nal system), TRH (hypothalamic–pituitary–thyroid
mone releasing hormone (GHRH) synergize to regulation) and dopamine (PRL secretion) all func-
stimulate growth hormone (GH) secretion, whereas tionthroughspecificGPCRs.Otherexampleswillbe
3
somatostatin serves to inhibit GH secretion covered in later chapters. These receptors represent
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
a superfamily of human membrane proteins. Drugs Desensitizationis reversibleby replacingcontinuous
thattargetthemaccountforapproximately30%ofthe GnRH treatment with an episodic, pulsatile stimula-
global market share of therapeutic drugs, with esti- tion. This will be described in more detail in
mated sales for 2011–2015 of approximately Chapter 3. A similar phenomenon is reported with
US$890billion(Hauseretal.,2017). stimulation of LH secretion with the neuropeptide
TheresponsivenessofGPCRstostimulationmay kisspeptin, which also binds to a GPCR (Jayasena
becompromisedinsomeneuroendocrinedisorders. etal.,2009;seeChapter3).
Receptor function is affected in two principal ways:
MutationsinGPCRGenes
(a)whenGPCRsaresubjectedtochronicstimulation
to produce tachyphylaxis, and (b) when mutations TheclinicalsignificanceofGPCRsintheneuroendo-
occur in the genes for receptor proteins or crine system is reinforced when taking into account
Gproteins. endocrine/neuroendocrinedisordersthatresultfrom
loss-of-functionorgain-of-functionmutationsinthe
ChronicStimulationandGPCRDownregulation
genesforreceptorproteinsorGproteins(Vassartand
For example, continuous stimulation of the human Costagliola,2011).Table1.1listsagroupofmutations
female pituitary with the releasing hormone GnRH of GPCRs relevant to endocrine diseases, together
downregulates (desensitizes) the normal response with the appropriate chapter where these receptors
such that LH secretion and ovulation is inhibited are discussed (based on data from Lania et al., 2006;
(Southworth et al., 1991). A major consequence of VassartandCostagliola,2011).Adetaileddiscussion
continuousstimulationofgonadotrophsisinhibition of gain-of-function GPCR mutations associated with
ofthenormalresponsethroughthelossofcellsurface endocrine disorders is covered elsewhere (Fukami
GnRH receptors (Engel and Schally, 2007). etal.,2018).
Table1.1 ClinicalandbiochemicalfeaturesofendocrinedisorderscausedbyGPCRmutations
Clinicalfeatures Biochemicalfeature GPCRaffected(typeof
mutation)
Thyroiddisorders(Chapter6)
Isolatedcentralhypothyroidismwithnormal NormalorlowTSH,lowfT absent TRHreceptor(inactivating)
4
pituitaryMRI TSHandprolactinresponsestoTRH
test
Completecongenitalhypothyroidism HighTSH,lowfT,nogoiter,no TRHreceptor(inactivating)
4
antibodiestothyroglobulinor
thyroperoxidase
Juvenilehyperthyroidismwithgoiter LowTSH,highfT,noantibodiesto TSHreceptor(activating)
4
thyroglobulinorTSHreceptor
Reproductivedisorders(Chapter3)
Delayedpuberty Lowsexsteroidsandlow–normal Kisspeptinreceptor(inactivating)
LHandFSHresponsivetoGnRHtest
Lowsexsteroidsandlow–normal GnRHreceptor(inactivating)
LHandFSHpoorlyresponsiveto
GnRHtest
Primaryamenorrheawithnormaldevelopmentof HighLH,normalorhighFSH,and LHreceptor(inactivating)
primaryandsecondarysexualcharacteristics lowestradiolandprogesterone
Maleprecociouspubertywithnormalpituitary HightestosteroneandlowLHand LHreceptor(activating)
MRI FSHwithprepubertalresponseto
GnRHtest
Primaryorearly-onsetsecondaryamenorrhea, HighLH,highFSH FSHreceptor(inactivating)
variabledevelopmentofsecondarysex
characteristicsandprematurearrestoffollicular
maturation
Ovarianhyperstimulationsyndromeduringinvitro None FSHreceptor(activating)
4
fertilization
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
Table1.1 (cont.)
Clinicalfeatures Biochemicalfeature GPCRaffected(typeof
mutation)
Obesity(Chapter4)
Early-onsetorsevereadultobesity,associatedwith Hyperinsulinemia Melanocortin4receptor
hyperphagia (inactivating)
Growthdisorders(Chapter8)
Dwarfismassociatedwithabdominaladiposity LowGHandinsulin-likegrowth GHRHreceptor(inactivating)
factor1,unresponsivetoGHRHtest
Waterbalancedisorders(Chapter9)
Nephrogenicdiabetesinsipidus Hypernatremia,lowurine V2R(inactivating)
osmolality,normalorhighVP
Nephrogenicsyndromeofinappropriate Hyponatremia,lowserum V2R(activating)
antidiuresis osmolality,inappropriatelyhigh
urineosmolality,undetectableVP
levels
Abbreviations:FSH,folliclestimulatinghormone;fT ,freethyroxine;GH,growthhormone;GHRH,growthhormonereleasing
4
hormone;GnRH,gonadotropinreleasinghormone;GPCR,Gprotein-coupledreceptor;LH,luteinizinghormone;MRI,magnetic
resonanceimaging;TRH,thyrotropinreleasinghormone;TSH,thyroidstimulatinghormone;VP,vasopressin;V2R,vasopressin
receptor2.
1.3 Tyrosine Kinase-Dependent
Leptin receptor dimer
Receptors LEPTIN
Plasma membrane
Peptide hormones such as leptin, PRL and GH (see
JAK JAK
Chapters 4, 7 and 8, respectively) do not bind to Cytoplasm P P
GPCRs. As shown in Figure 1.5, the receptor struc- P P
tures – in this case the leptin receptor dimer – have P P SOCS3
onlytwotransmembranedomains.Leptinbindingto –
STAT STAT
a single transmembrane protein induces receptor
dimerization,whichthenstimulatesatyrosinekinase
pathwayratherthantheGproteinsignalingshownin P STAT
Figure1.3.Forleptin,PRLandGH,thisisthesecond STAT P
messengerJAK/STATpathway(fordetailsoftheGH
systemseeChapter8;Figure8.12). Nucleus
Forexample,bindingofleptintoitsreceptoracti- P STAT
Gene
vates (phosphorylates) Janus kinase (JAK) proteins STAT P expression
that are docked on the intracellular domain.
Activated JAKs then phosphorylate the signal trans-
ducerandactivatoroftranscription(STAT)familyof Figure1.5 LeptinreceptorandtheJAK/STATpathway.Bindingof
transcriptionfactors.DimerizationofSTATproteins leptintoitsreceptordimeractivates(phosphorylates;P)JAK
proteins.ActivatedJAKsthenphosphorylatetheSTATfamilyof
precedes translocation to the nucleus where binding
transcriptionfactors.DimerizationofSTATproteinsprecedes
to response elements on DNA modulates transcrip- translocationtothenucleuswherebindingofthetranscription
tion of target genes. Unlike the leptin receptor, the factortoresponseelementsonDNAmodulatestranscriptionof
targetgenes.Alsoincludedisanegativefeedbacksystemwhere
PRLandGHreceptorsexistaspreformeddimers(see
geneexpressionofSOCS3modulatesleptinstimulation.Image
Figure8.12forGH,andBrooksandWaters,2010)but reproducedwithpermission(Dodingtonetal.,2018).Abbreviations:
also employ the JAK/STAT pathway following bind- STAT,signaltransducerandactivatoroftranscription;SOCS3,
suppressorofcytokinesignaling3.
ingoftheligand(Bernardetal.,2015).
5
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
Clinical Significance of Tyrosine insensitivity – mutations in the intracellular STAT5
gene (see Figure 8.12) – is now described; that is, the
Kinase-Dependent Receptors
intracellular signaling pathway is defective (Hwa,
The clinical importance of leptin, PRL and GH is 2016).Loss-of-functionmutationsinthePRLreceptor
describedintheappropriatechapters.Theclinicalcon- have also been described (Bernard et al., 2015). Such
sequences of abnormal receptor signaling are pro- patientspresentwithhyperprolactinemia,possiblydue
found, and defects, either at the receptor or in the to the inability of PRL to exert negative feedback on
intracellularpathway,appearasahormonedeficiency. pituitarylactotrophs.
For example, as described inChapter 4, obese indivi-
dualsareinsensitivetotheirownhighlevelsofleptin. 1.4 Intracellular Receptors for
By analogy with the insulin resistance seen in type 2
Steroid Hormones
diabetes,thecommonformsofdiet-relatedobesityare
thoughttobeattributableto“leptinresistance,”astate Steroid hormones (e.g., testosterone, estradiol and
inwhichmultiplecellularprocessesblockleptinrecep- cortisol; Figure 1.6) and thyroid hormones (see
torsignaling(Myers etal., 2010).Thus, highlevels of Figure 6.5) are fat-soluble molecules transported in
endogenous leptin, derived from the increased fat thebloodboundtocarrierproteins.
mass,failtoreducefoodintakeorbodyweight.Also, Steroid hormones readily diffuse through cell
patients with mutations in the leptin receptor are membranes into any cell in the body, but only their
severelyobeseandeffectivelyleptin-free,eventhough targetcells,inbrainandpituitaryforexample,possess
leptin levels are high (Farooqi et al., 2007). In these specific intracellular receptors. These receptors have
cases, leptin is unable to signal to downstream path- common structural elements and belong to
ways. Due to loss-of-function mutations in the GH asuperfamilyofreceptorproteins(Figure1.7).
receptor (Rosenfeld et al., 2007; Brooks and Waters, Eachreceptorproteincontainsahormonebinding
2010), patients insensitive to GH (Laron syndrome) domain (HBD) that is specific for each hormone.
show severe growth failure and insulin-like growth Thus,forexample,thehumanglucocorticoidreceptor
factor1(IGF-1)deficiency(seeChapter8).Oversixty (hGR)bindscortisolintheHBD,whereastheproges-
loss-of-function mutations in the GH receptor have terone receptor (hPR) recognizes only progesterone.
been reported, although a new cause of GH Binding of the hormone to its specific receptor
Figure1.6 Chemical
structuresofthemajorsteroid
hormones.Fourprincipal
familiesofsteroidhormones
are:androgens(e.g.,
testosterone),estrogens(e.g.,
estradiol),glucocorticoids
(e.g.,cortisol)andmineralo-
corticoids(e.g.,aldosterone).
Theyareallderivedfrom
cholesterol.Animportant
familynotshownisthe
progestogens(e.g.,
progesterone).Notethatthe
femalesexhormoneestradiol
isformedbyaromatization
fromthemalehormone
testosterone.Copyright
A.Pincock.
6
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
hAR NTD DBD H HORMONE BINDING DOMAIN
100 100 100
hERα NTD DBD H HORMONE BINDING DOMAIN
15 51 20
hERβ NTD DBD H HORMONE BINDING DOMAIN
15 56 22
hGR NTD DBD H HORMONE BINDING DOMAIN
15 77 50
hPR 15 NTD 80DBD H 53HORMONE BINDING DOMAIN
Figure1.7 Structuresofmembersofthehumansteroidreceptorsuperfamily.Theseintracellularreceptorsconsistofasinglepolypeptidechain
andallofthefamilymemberscontainahormonebindingdomainthatisspecificforeachhormone.Forexample,hGRbindscortisolin
thisregion,whereasthehPRwillonlyrecognizeprogesterone.TheDBDenablesthehormone-receptorcomplextobindtotheHRE(see
Figure1.8)onatargetgene.Thehingeregion(H)isimportant,alongwiththeDBD,fornuclearlocalizationofthereceptor,andtheNTDis
crucialfortheactivationofgenetranscriptiononcethehormone-receptorcomplexreachesthenucleusandbindswiththeHRE.Numbers
indicatethedegreeofstructuralhomologyineachdomain,comparedwiththehAR(McEwanandBrinkmann,2016).Abbreviations:DBD,DNA
bindingdomain;hAR,androgenreceptor;hERα,estrogenreceptorα;hERβ,estrogenreceptorβ;hGR,glucocorticoidreceptor;hPR,
progesteronereceptor;HRE,hormoneresponseelement;NTD,aminoterminaldomain.
enables the DNA binding domain (DBD) to interact Estrogen Receptors
with specific sites on target genes called hormone
Itisbeyondthescopeofthistexttoprovideadescription
response elements (HRE; see Figure 1.8). The hinge
of the clinical role of all of the nuclear receptors illu-
region (H) appears to be important, along with the
stratedinFigure1.7,andtheestrogenreceptor(ER)will
DBD,fornuclearlocalizationofthereceptor,andthe
beusedhereasanexample.ERsexistinthreeforms,two
aminoterminaldomain(NTD)iscrucialfortheacti-
ofwhicharenuclear(ERαandERβ,alsotermedESR1
vation of gene transcription once the hormone-
and ESR2; Figure 1.7) and the third, located in cell
receptorcomplexreachesthenucleusandbindswith
membranes, is a GPCR. The latter – termed the
theHRE(McEwenandBrinkmann,2016).Notethat
Gprotein-coupledER-1(GPER-1)–isarelativenew-
the receptor proteins have no biological activity until
comer to ER physiology, and these receptors permit
theybindtoahormone;thatis,thehormone-receptor
rapid, non-genomic (non-nuclear), cellular responses
complexactsasatranscriptionfactoratspecificsites
to estrogen treatment. There is evidence of
(HRE) on target genes. Figure 1.8 illustrates the
a physiological role for GPER-1 in the reproductive,
sequenceofeventsthatoccurwhenasteroidhormone
nervous, endocrine, immune and cardiovascular sys-
diffusesintotargetcells,suchaspituitaryorhypotha-
tems(ProssnitzandBarton,2011),andGPER-1appears
lamus. The hormone is released from the binding
to be a promising and novel therapeutic target and
globulin (BG), enters the cell and binds to a specific
prognosticindicator(Barton,2016).Membranerecep-
receptor (R) in the cell cytosol. The unoccupied R is
tors for androgens, glucocorticoids (GCs), aldosterone
coupled to a so-called molecular chaperone (heat
andthyroidhormonehavealsobeendescribed.
shock protein 90; HSP90) that ensures the receptor
ERαandERβ,theproductsoftwodistinctgenes,
isstabilizedinthecorrectshape.Followinghormone
are localized in many tissues (Figure 1.9), with ERα
binding to the receptor-HSP90 complex, the HSP90
especially concentrated within the reproductive sys-
dissociates and the remaining hormone-receptor
tem (hypothalamus, pituitary, breast and uterus).
complex dimerizes. The dimer then enters the cell
Details of their functional role in estrogen feedback
nucleus where it attaches to an HRE to modify gene
and the regulation of anterior pituitary secretion of
expression and the export of mRNA into the cell
gonadotropins through the menstrual cycle is out- 7
cytosolwhereitistranslatedintoprotein.
linedinChapter3.
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Chapter1: BasicPrinciplesinClinicalNeuroendocrinologyI:ReceptorMechanisms
Figure1.8 Schematicviewofasteroid
hormoneinteractingwithatargetcell.
Thehormoneisreversiblyboundto
abindingglobulin(BG)beforethefree
hormonefreelydiffusesthroughthecell
membrane.Theunoccupiedsteroidrecep-
tor(R)iscoupledtoamolecularchaperone
(HSP90)thatstabilizesRinthecorrect
shape.Whenthehormonebindstothe
receptor-HSPcomplex,theHSPdissociates
andtheremaininghormone-receptor
complexdimerizesbeforeitentersthecell
nucleus.Thehormone-receptordimerthen
bindstotargetgenesviaaspecificHRE.
VariousfactorssuchasGTFsandRNAPOLII
assistininducinggenetranscriptionand
theexportofmRNAintothecellcytosol
whereitistranslatedintoprotein.
Abbreviations:GTF,generaltranscription
factor;HSP,heatshockprotein;HSP90,heat
shockprotein90;mRNA,messengerRNA;
POLII,polymeraseII;RNA,ribonucleicacid.
ThisfigurerevealsthatERsareimplicatedinreg- inflammation and osteoporosis (Paterni et al., 2014;
ulating multiple complex physiological processes in Warneretal.,2017).
humans,andabnormalERfunctionleadstoavariety
ofdiseases, suchas cancer,metabolic and cardiovas- Hormone Resistance
cular disease, neurodegeneration, inflammation and
This section uses the estrogen and GC receptors as
osteoporosis(Jiaetal.,2015).
examples of the clinical consequences of hormone
Clinical significance: Using the menopause as
resistance. Other well-described examples include
aspecificexample,estrogendeprivationhasprofound
androgen receptor insensitivity (testicular feminiza-
effects particularlyin thecentralnervous system;for
tion syndrome; Hiort, 2013) and thyroid hormone-
example, vasomotor symptoms such as hot flashes
receptor insensitivity (Ortiga-Carvalho et al., 2014;
andnightsweats,developmentofanxiety,depression,
seealsoChapter6).
poorqualityofsleepandmigraine.Figure1.10illus-
tratesthewidespreadinfluenceofestrogendepletion Estrogens
(Monteleoneetal.,2018).
ERresistanceappearstobeunknownwithintheneu-
Estrogenreplacementatthemenopauseinevitably roendocrine system. However, mutations in ERα in
influencesmanysystems,somenotwithoutrisk,asin
metastaticbreastcancerarewell-describedandresult
the possibilityofbreastcancer(Warneret al.,2017).
fromlong-termtreatmentwithantiestrogens,suchas
Selective targeting of ERα and ERβ appears to be
tamoxifen, and drugs such as fulvestrant that
a promising way to achieve beneficial estrogenic degrades ERα (Huang et al., 2017). Drug-induced
effects while avoiding unwanted side effects. ERβ
estrogenresistancecouldtaketheformofchangesin
selectiveagonistsarenowavailablethathavenoeffect downstreamsignalingorasintrinsicactivationofERα
inbreasttissuebutmaybetherapeuticagentsconsid-
in the absence of estradiol. It is possible that tamox-
ered for prevention and treatment of cancer, meta- ifenorfulvestrantcouldaffecthypothalamicorpitui-
8 bolicandcardiovasculardiseases,neurodegeneration, taryERαreceptors.
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